Acamprosate Inhibits the Binding and Neurotoxic Effects of Trans-ACPD, Suggesting a Novel Site of Action at Metabotropic Glutamate Receptors

Harris, Barton R.; Prendergast, Mark A.; Gibson, D. Alex; Rogers, Dennis T.; Blanchard, John; Holley, Robert C.; Fu, May C.; Hart, Stewart R.; Pedigo, Norman W.; Littleton, John M.

doi:10.1097/00000374-200212000-00004

Cited by 46 publications

(72 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…(ii) The finding that MPEP evokes anxiolytic-and antidepressant-like effects in rats (Tatarczynska et al, 2001;Pilc et al, 2002) also has implications for the treatment of alcoholism due to the high comorbidity with these psychiatric disorders. (iii) Furthermore, Harris et al (2002) showed that acamprosate exhibits binding and functional characteristics that are consistent with an mGluR5 antagonist. These authors further speculate that acamprosate's ability to reduce relapse rates in alcoholic patients may result from its alterations in glutamatergic neurotransmission through mGluR5s.…”

Section: Discussionmentioning

confidence: 92%

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

Bäckström

Bachteler

Koch

et al. 2003

Neuropsychopharmacol

235

178

View full text Add to dashboard Cite

The glutamatergic system plays an important role in mediating neurobehavioral effects of ethanol. Metabotropic glutamate receptors subtype 5 (mGluR5) are modulators of glutamatergic neurotransmission and are abundant in brain regions known to be involved in ethanol self-administration. Here, we studied the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a highly potent, noncompetitive mGlu5 receptor antagonist, on voluntary ethanol consumption and relapse behavior. For this purpose, we used two models for the measurement of relapse behavior: (i) reinstatement of ethanol-seeking behavior by drug-associated cues and (ii) the alcohol deprivation effect in long-term ethanol-consuming rats. In the first set of experiments, rats were trained to lever press for ethanol in the presence of a distinct set of cues. After extinction, the animals were exposed to the respective cues that initiated reinstatement of responding. A response-contingent ethanol prime further enhanced responding compared to the conditioned cues alone. Under these conditions, MPEP (0, 1, 3, and 10 mg/kg) attenuated ethanol seeking significantly and in a dose-related manner. However, at the highest dose, MPEP also decreased the number of inactive lever responses. In the second set of experiments, rats with 1 year of ethanol experience and repeated deprivation phases were used. A subchronic treatment with MPEP (twice daily; 0, 3, and 10 mg/kg) resulted in a significant and dose-dependent reduction of the alcohol deprivation effect (ADE). Although the same MPEP treatment regimen decreased baseline drinking, this effect was not as pronounced as on the ADE. These results show in two commonly used models of relapse to ethanol that pharmacological targeting of mGlu5 receptors may be a promising approach for the treatment of alcoholism.

show abstract

Section: Discussionmentioning

confidence: 92%

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

Bäckström

Bachteler

Koch

et al. 2003

Neuropsychopharmacol

235

178

View full text Add to dashboard Cite

show abstract

“…Several possible modes of action of acamprosate have been described (Mann et al, 2008); however, a body of evidence suggests that acamprosate interacts with NMDA receptors and/or mGluR5 (Mann et al, 2008;Harris et al, 2002;Madamba et al, 1996). To test these putative interactions, we applied an extensive screening panel.…”

Section: Resultsmentioning

confidence: 99%

“…Many molecular candidate targets have been described (Spanagel and Vengeliene, 2013;De Witte et al, 2005;Mann et al, 2008) but the only accumulated evidence was found with respect to an interaction with the glutamate system. In concert, these studies suggest that acamprosate attenuates hyperglutamatergic states that occur during early and protracted abstinence, possibly involving N-methyl-D-aspartate (NMDA) receptors and metabotropic glutamate receptor 5 (mGluR5) (Spanagel and Vengeliene, 2013;De Witte et al, 2005;Mann et al, 2008;Rammes et al, 2001;Harris et al, 2002). A prominent theory in the alcohol research field posits that chronic alcohol consumption leads to glutamatergic dysfunction.…”

Section: Introductionmentioning

confidence: 99%

“…Instead, calcium is the active moiety of acamprosate! In the first set of experiments, we tested the putative interactions of acamprosate with NMDA receptors and mGluR5 (Mann et al, 2008;Harris et al, 2002;Madamba et al, 1996). From these experiments, we have to conclude that the proposed glutamate receptor interactions of acamprosate cannot sufficiently explain the anti-relapse action of this drug.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Acamprosate Produces Its Anti-Relapse Effects Via Calcium

Spanagel

Vengeliene

Jandeleit³

et al. 2013

Neuropsychopharmacol

125

View full text Add to dashboard Cite

Alcoholism is one of the most prevalent neuropsychiatric diseases, having an enormous health and socioeconomic impact. Along with a few other medications, acamprosate (Campral-calcium-bis (N-acetylhomotaurinate)) is clinically used in many countries for relapse prevention. Although there is accumulated evidence suggesting that acamprosate interferes with the glutamate system, the molecular mode of action still remains undefined. Here we show that acamprosate does not interact with proposed glutamate receptor mechanisms. In particular, acamprosate does not interact with NMDA receptors or metabotropic glutamate receptor group I. In three different preclinical animal models of either excessive alcohol drinking, alcohol-seeking, or relapse-like drinking behavior, we demonstrate that N-acetylhomotaurinate by itself is not an active psychotropic molecule. Hence, the sodium salt of N-acetylhomotaurinate (i) is ineffective in alcohol-preferring rats to reduce operant responding for ethanol, (ii) is ineffective in alcohol-seeking rats in a cue-induced reinstatement paradigm, (iii) and is ineffective in rats with an alcohol deprivation effect. Surprisingly, calcium salts produce acamprosatelike effects in all three animal models. We conclude that calcium is the active moiety of acamprosate. Indeed, when translating these findings to the human situation, we found that patients with high plasma calcium levels due to acamprosate treatment showed better primary efficacy parameters such as time to relapse and cumulative abstinence. We conclude that N-acetylhomotaurinate is a biologically inactive molecule and that the effects of acamprosate described in more than 450 published original investigations and clinical trials and 1.5 million treated patients can possibly be attributed to calcium.

show abstract

“…Finally, postsynaptic aspects of corticoaccumbens glutamatergic signaling regulate either the self-administration of various drugs of abuse, or the potential to relapse to drug-seeking, in both humans and laboratory animals. Acamprosate, a mixed antagonist at the NMDA ionotropic glutamate receptor (iGluR) and the mGluR5 subtype of the Group1 metabotropic glutamate receptor (mGluR) [71,72], is clinically effective at treating alcoholism [73,74] and may prove to be effective for treating psychomotor stimulant and opiate addiction [75,76]. Moreover, direct pharmacological manipulation of glutamate receptors within the PFC or the NAC result in reduced behavioral responsiveness to various drugs of abuse, including cocaine [48,50,53,[77][78][79]; but see 80], alcohol [e.g., 44, 81,82], amphetamines [e.g., [83][84][85][86][87][88][89] and opiates [90-92, but see 79], and systemic administration of antagonists of glutamate receptors blocks several aspects of nicotine reward in laboratory animals [e.g., 93-100, but see 101].…”

Section: Introductionmentioning

confidence: 99%

Homers regulate drug-induced neuroplasticity: Implications for addiction

Szumlinski

Ary

Lominac

2008

Biochemical Pharmacology

118

160

View full text Add to dashboard Cite

Drug addiction is a chronic, relapsing disorder, characterized by an uncontrollable motivation to seek and use drugs. Converging clinical and preclinical observations implicate pathologies within the corticolimbic glutamate system in the genetic predisposition to, and the development of, an addicted phenotype. Such observations pose cellular factors regulating glutamate transmission as likely molecular candidates in the etiology of addiction. Members of the Homer family of proteins regulate signal transduction through, and the trafficking of, glutamate receptors, as well as maintain and regulate extracellular glutamate levels in corticolimbic brain regions. This review summarizes the existing data implicating the Homer family of protein in acute behavioral and neurochemical sensitivity to drugs of abuse, the development of drug-induced neuroplasticity, as well as other behavioral and cognitive pathologies associated with an addicted state.

show abstract

Acamprosate Inhibits the Binding and Neurotoxic Effects of Trans-ACPD, Suggesting a Novel Site of Action at Metabotropic Glutamate Receptors

Cited by 46 publications

References 59 publications

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

Acamprosate Produces Its Anti-Relapse Effects Via Calcium

Homers regulate drug-induced neuroplasticity: Implications for addiction

Contact Info

Product

Resources

About